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Medicine in Novel Technology and Devices 22 (2024) 100309

Contents lists available at ScienceDirect

Medicine in Novel Technology and Devices

journal homepage: www.journals.elsevier.com/medicine-in-novel-technology-and-devices/

Novel succinoylated carboxymethyl guar gum nanocarriers of glimepiride

for controlling type-2 diabetes
Harsh Yadav a, Biswajit Maji b, Sabyasachi Maiti a, *
a
Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak, Madhya Pradesh, India
b
Department of Chemistry, Indira Gandhi National Tribal University, Amarkantak, Madhya Pradesh, India

A R T I C L E I N F O A B S T R A C T

Keywords: In this study, guar gum (GG) was chemically modified to its carboxymethyl derivative, which was then esterified
Guar gum with octenyl succinic anhydride (OSA) using a nucleophilic catalyst 4-dimethylaminopyridine (DMAP) to render
Glimepiride the derivative amphiphilic characteristics. The carboxymethyl guar gum (CMGG) and succinoylated CMGG was
Octenyl succinic anhydride
characterized using Fourier transform infrared spectroscopy (FTIR) spectroscopy. The amphiphilic CMGG syn-
Anti-diabetic efficacy
thesized using DMAP/OSA ratio of 0.5:1 (CMGGOSA-I), was found to be non-toxic. The amphiphilic guar gum
self-assembled in water to form nanocarriers with mean diameter of 430 nm and zeta potential of
19.0 mV.
Transmittance electron microscope (TEM) image showed spherical nature of the developed CMGGOSA-I nano-
carriers. In presence of amphiphilic CMGG, the aqueous solubility of glimepiride was enhanced by about 67-fold.
The nanocarriers released glimepiride in simulated gastrointestinal fluids for a period of more than 24 h,
following Higuchi's kinetics. Korsmeyer-Peppas modeling of the drug release data revealed that a combination of
swelling and diffusion mechanism was operative in the event of drug release. In streptozotocin-induced diabetic
rat model, the nanocarriers outperformed pure drug suspensions in terms of anti-diabetic activity, which lasted up
to 24 h. Overall; the newly synthesized amphiphilic CMGG nanocarriers demonstrated controlled drug release
properties and showed promise for controlling type-2 diabetes.

1. Introduction water solubility, hence improving bioavailability. They are simply and
consistently manufactured in large quantities [4]. When the
Oral administration of medicinal agents is by far the simplest and surfactant-based core-shell nanocarriers are diluted, they rapidly break
most convenient method of medication delivery, particularly in chronic apart, resulting in premature drug leakage and precipitation in situ. The
therapy [1]. In the case of poorly water-soluble drugs, the dissolving limitations of surfactant-based core-shell nanoscale drug carriers
period in the gastrointestinal contents may exceed the transit time to the prompted a quest for amphiphilic nanocarriers with much improved
intended absorptive sites [2]. As a result, drug dissolution is frequently stability and solubilizing capability.
the rate-limiting phase that determines the drug's bioavailability. This The usage of biopolymer-based nanocarriers has received a lot of
presents a significant problem for effectively delivering poorly attention because of the polymers' tremendous diversity, biocompati-
water-soluble drugs orally. bility, biodegradability, and the variety of functional groups they have
The amphiphilic nanocarriers are made up of an inner core of con- for pilot molecule conjugation [5]. Guar gum (GG) is a seed poly-
structed hydrophobic segments capable of solubilizing lipophilic com- saccharide made up of linear (1 → 4)-β-D-mannopyranosyl chains, with
pounds and an outside hydrophilic corona that acts as a stabilizing pendent α-D-galactopyranosyl units connected by (1 → 6) links. The ratio
interface between the hydrophobic core and the external aqueous envi- of mannose to galactose units in guar gum is around 2:1 [6]. It is
ronment [3]. The hydrophilic shell enhances the pharmacological char- biocompatible, biodegradable, non-toxic, inexpensive, and chemically
acteristics of polymeric formulations by improving dispersibility of adaptable, making it an attractive material for designing drug delivery
nanocarriers and avoiding interactions with cellular materials. These formulations [7].
drug carriers physically entrap sparingly soluble medicines and carry Carboxymethylation, in particular, has been shown to increase water
them to the target site at concentrations that may surpass their inherent solubility while decreasing solution viscosity relative to the natural

* Corresponding author.
E-mail address: [email protected] (S. Maiti).

https://doi.org/10.1016/j.medntd.2024.100309
Received 8 March 2024; Received in revised form 19 May 2024; Accepted 23 May 2024
2590-0935/© 2024 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.
0/).
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H. Yadav et al. Medicine in Novel Technology and Devices 22 (2024) 100309

polysaccharide [8]. When this hydroxyl group-rich polymer is mixed added to the reaction mixture in portions over an hour and a half while
with water, it generates hydrogen bonds, which add viscosity and thicken stirring with a glass rod to keep the bath temperature between 15 and 18

the solution [9]. Chemical modification of natural gums removes C. The temperature of the reaction mixture was gradually increased to
intrinsic shortcomings that may limit their general use for widespread 65–70  C and blended for an additional hour. Finally, the reaction
applications. The carboxymethylation could significantly improve the mixture was cooled and rinsed with 50 mL of 80 % methanol solution.
solubility of GG in water. Further, the non-covalent hydrogen-bonding The solution's pH was neutralized by adding 1 M HCl solution dropwise.
interactions between hydrophilic shell of CMGG and water could provide Finally, the yellowish material was filtered, washed, and dried for 24 h to
structural stability to the self-assembled nanocarriers. Previous studies produce CMGG. The reaction scheme is shown in Fig. 1.
pointed out that the hydrogen bonding interactions with water could
affect physicochemical properties of the compound [10–12]. 2.3. Determination of degree of substitution (DS)
The United States Food and Drug Administration (US FDA) has
cleared 1-octenylsuccinic anhydride (OSA) for use in food. Previously, The degree of substitution of CMGG was determined using titrimetry
the drug delivery capability of amphiphilic octenylsuccinated poly- according to a previously reported method in the literature [24–26].
saccharides such as konjac glucomannan [13], dextrin [14], curdlan Sodium CMGG (1.5 g) was treated with 50 mL of 2 M HCl, and
[15], starch [16], maize dextrin [17], carboxymethyl curdlan [18], and magnetically stirred for 2 h to convert it to hydrogen-form. The H-CMGG
carboxymethyl sesbania gum [19] was reported in the literature. The dispersion was isolated and dried at 60  C for 2 h. Dry H-CMGG (0.5 g)
literature describes the manufacture of amphiphilic guar gum nano- was dissolved in standardized 50 mL 0.1 M NaOH solution and then
carriers after hydrophobization using poly(ε-caprolactone) conjugation titrated with a 0.1 M HCl, using phenolphthalein and the DS was
[20] and acetylation [21]. estimated:
Glimepiride is a sulfonylurea oral anti-diabetic medication (third
generation) that is used to treat type-2 diabetes. Due to its limited water CNaOH VNaOH
CHCl VHCl
wa ¼
solubility and high permeability, it is classified as a class II medication m
under the Biopharmaceutical Classification System (BCS) [22]. Glime-
piride's oral dose formulations confront hurdles due to its low water DS ¼ 162wa = ð5900
58wa Þ
solubility, poor dissolution profiles, and thus reduced bioavailability
[23]. The development of glimepiride nanocarriers may improve its 2.4. Succinoylation of CMGG
solubility characteristics in gastrointestinal fluids, as well as
bioavailability. The succinoylated derivative of CMGG was performed using ionic
There are currently no studies in the art towards the development of liquid BMIMCl and OSA in the presence of DMAP. Accurately weighed,
glimepiride-loaded nanoparticles based on octenylsuccinoylation of CMGG (1.0 g) was dissolved in 10 mL distilled water and was then
carboxymethyl guar gum (CMGG). In this study, we developed amphi- transferred to a 2-neck round bottom flask containing 5.0 g of BMIMCl
philic octenylsuccinic acid-modified CMGG nanocarriers and tested their and the mixture was stirred at 80  C for 1 h. Then, 3 mL OSA (3.0 g,
controlled drug delivery capabilities and in vivo performance. 14.28 mmol) and DMAP (0.87 g; 7.14 mmol, 0.5 eqv. to OSA) were added
and stirred for further 3–4 h. The slurry was filtered, washed with iso-
2. Materials and methods propanol 3-times followed by ethanol 2–3 times. The wet mass was dried
to obtain solid white powder. Similarly, the guar gum double derivative
2.1. Materials was prepared using equal DMAP (1.75 g, 14.3 mmol): OSA (3 g, 14.3
mmol) molar ratio. The product obtained with DMAP: OSA molar ratio of
Guar gum and glimepiride was purchased from Sigma-Aldrich. 1- 0.5:1 and 1:1 was designated as CMGGOSA-I and CMGGOSA-II, respec-
butyl-3-methylimidazoliumchloride (BMIMCl) and 2-octen-1-ylsuccinic tively. The reaction scheme is shown in Fig. 2.
anhydride (OSA) were purchased from Aldrich. Streptozotocin was pro-
cured from HiMedia Laboratories Pvt. Ltd., Mumbai, India. Nicotinamide 2.5. Acute toxicity study
was purchased from Avra Synthesis Pvt., Ltd., Hyderabad, India. Mono-
chloroacetic acid was purchased from Central Drug House (P) Ltd., New The acute toxicity of CMGG, CMGGOSA-I and CMGGOSA-II was
Delhi, India. Other reagents used in this investigation of AR grade. assessed in Balb/c mice for a period of two weeks. The acute toxicity
testing was done on sixty mice of either sex. The test sample was
2.2. Synthesis of carboxymethyl guar gum (CMGG) administered by oral gavage to each mice of respective treatment group
using oral feeding needle and syringe of appropriate size. The test sample
5.0 g of GG was sprinkled into 17 mL of cold alkaline water (7.5 g of was dissolved in constant volume (10 mL/kg body weight) of vehicle and
NaOH). Monochloroacetic acid (3.75 g) solution in 8.5 mL water was administered to each animal over a period of 10–15 s. The study protocol

Fig. 1. Scheme for the synthesis of CMGG.

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H. Yadav et al. Medicine in Novel Technology and Devices 22 (2024) 100309

Fig. 2. Scheme for the synthesis of CMGGOSA-I.

was approved by institutional animal ethics committee of Pretox order [28], and Higuchi [29] kinetic models. In addition, the first 60 %
Research Centre, Gujarat, India (Ref. No. PRC/IAEC/2021/01/XII/005). drug release data was fitted into Korsmeyer-peppas model equation in
The guidelines for animal experiments comply with the National In- order to evaluate drug release mechanism from the nanocarriers [30].
stitutes of Health guide for the care and use of Laboratory animals.
Mt
¼ ktn
M∞
2.6. Measurement of particle size and zeta potential
where left hand side of the equation indicates the fractional solute release
The liquid sample of CMGGOSA-I was sonicated for 15 min and the at time t, k is a constant and n is the diffusion exponent. Non-Fickian or
hydrodynamic diameter of the sample was measured by dynamic light anomalous mechanism was indicated when 0.43 < n < 0.89 [31].
scattering (Litesizer™ 500, Anton Paar) with a detection angle of 90⁰ at
25  C. The sample was filled in Omega cuvette and zeta potential was also
2.11. In vivo anti-diabetic activity
measured.
Male Wistar rats (200–250 g, 10–12 weeks old) were used for this
2.7. TEM imaging study after getting approval of the protocol by Institutional Animal Ethics
Committee (Reg. No. 2004/GO/ReBi/S/18/CPCSEA) vide Ref. No.
The CMGGOSA-I samples were bath sonicated for 15 min and the IGNTU/IAEC/2021/26 dated December 10, 2021. The guidelines for
sample (μL) was placed on a copper grid, dried and imaged (TECNAI G20 animal experiments comply with the National Institutes of Health guide
HR-TEM, Thermo Scientific) at an operational voltage of 200 kV. for the care and use of Laboratory animals. The animals remained fasted
for 12 h prior to commencement of the study. The nicotinamide (110 mg/
2.8. Loading of glimepiride into CMGGOSA-I nanocarriers kg body weight) dissolved in 1 mL saline was given intraperitoneally 15
min before streptozotocin administration [32].
CMGGOSA-I (20 mg) was dissolved in 10 mL of purified water. A 2.5 The streptozotocin at a dose of 50 mg/kg body weight, dissolved in
mL drug solution in chloroform (2 mg/mL) was dropped into the cold citrate buffer (pH 4.5) was administered by intraperitoneal injection
amphiphilic polymer solution through a needle; while swirling continu- for the induction of diabetes. Because streptozotocin can cause deadly
ously for 6 h. The dispersion was passed through 0.45 μm membrane hypoglycemia due to excessive pancreatic insulin release, after 1 h of
syringe filter and the filtrate was diluted 100 times with phosphate buffer streptozotocin/nicotinamide injection, rats were given a 10 % w/v su-
(pH 6.8) for the measurement of absorbance at 226 nm crose solution to prevent rapid hypoglycemia. After 3 days of strepto-
spectrophotometrically. zotocin/nicotinamide administration, induction of diabetes was
confirmed by determining blood glucose levels (>500 mg/dL) [33].
2.9. In vitro release of glimepiride Eighteen rats were distributed randomly into three groups of six each.
Group 1 was treated as control (fed with normal water), Group 2 received
5 mL of drug-loaded CMGGOSA-I carriers was placed in an overnight- pure glimepiride suspension at an oral dose of 0.1 mg/kg body weight
soaked dialysis bag (MWCO 12–14 kDa) and immersed in 200 mL of HCl and Group 3 was treated with the CMGGOSA-I formulation containing
solution (pH 1.2). The release media was replaced with a phosphate glimepiride equivalent to 0.1 mg via oral gavages [34].
buffer solution (pH 6.8) after 2 h. The releasing media was swirled at 150 Blood were obtained at 1-h intervals for 24 h, and glucose levels were
rpm. 5 mL sample was taken periodically and promptly refilled with the checked with commercial blood glucose test strips. The animal dose was
equivalent volume of corresponding media. The sample was analyzed calculated using the method reported earlier [35,36].
with a UV–Vis spectrophotometer at 226 nm.
2.12. Statistical analysis
2.10. Drug release kinetics
All studies were done in triplicate, and the outcomes were reported as
The in vitro drug release data were fitted into zero order [27], first mean with standard deviation (SD). The blood glucose lowering activity

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H. Yadav et al. Medicine in Novel Technology and Devices 22 (2024) 100309

parameters, including inductive effects, steric effects, and conformation

[46]. As a result, a modest degree of O-carboxymethyl substitution is
expected.
The LD50 value of CMGG and CMGGOSA-I was not established based
on the toxicity studies because no death was detected following single
oral dose of 2000 mg/kg body weight. Consequently, these modified
polymers were non-toxic up to 2000 mg/kg body weight. However, after
single oral dose, the LD50 value of CMGGOSA-II was calculated to be
908.8 mg/kg body weight with fiducial limits of error ranging from 72.6
% to 137.7 % using Probit (Microsoft office excel 2007 software). Thus, it
was clear that the optimal ratio of DMAP to ionic liquid for the synthesis
of CMGGOSA would be 0.5:1, with no evidence of oral toxicity at doses
greater than 2000 mg/kg body weight. As a result, future research using
CMGGOSA-II was restricted.
The zeta potential is a trustworthy indicator of the stability of
colloidal dispersion. A physically stable suspension can be obtained when
the absolute value of the zeta potential is larger than or equal to 20 mV
[47]. The TEM image of CMGGOSA-I nanocarriers is shown in Fig. 4. The
Fig. 3. FTIR spectra of (a) CMGG; (b) CMGGOSA.
particles seemed precisely spherical, with a smooth surface morphology.
The average hydrodynamic diameter of the particles was 430 nm, with a
was analyzed by one way analysis of variance and then by Tukey's tests
PDI (polydispersity index) of 30.7 %. The colloidal dispersion of
(GraphPad Prism, version 10). The difference was significant when p <
CMGGOSA-I had a zeta potential of
19.0 mV. As to the instructions, a
0.05.
result of 10 % or less implies a monodisperse sample. Hence, the ester-
ified guar gum dispersion was not in a monodisperse form. As evident,
3. Results and discussion
the particle diameter obtained after TEM imaging was less than that
measured using Litesizer. The discrepancy in diameter measured by both
GG interacts with water molecules, causing entanglement of polymer
techniques was attributed to differences in sample preparation methods.
strands and increased viscosity. As the strength of gum increases, so does
Dynamic light scattering (DLS) measured the size of the sample while it
the entanglement, which causes gelling or thickening. Even a 1 %
was fully wet (swollen), whereas TEM measured the size when it was
aqueous dispersion of high-quality guar gum can have viscosity of up to
dehydrated (dry) [48].
10,000 cP [7]. To address this issue and use it in medicinal applications,
Glimepiride has extremely low water solubility (~ 4 μg/mL at 37  C)
the native gum was chemically modified to CMGG (Fig. 1). The modified
[49,50]. After integration into CMGGOSA-I nanocarriers, glimepiride's
gum was then converted into CMGGOSA by ester bond formation (Fig. 2).
water solubility was 269.6  14.69 μg/mL. As a result, the water solu-
The synthesis of hydrophilic CMGG was verified using FTIR analysis
bility increased by approximately 67-fold. Drug entrapment efficiency
(Fig. 3a). A broad signal at 3280 cm
1 in its spectrum was linked to
was 53.93  2.94 %. The glimepiride release profile is illustrated in
hydroxyl group -O-H stretching. The peak at 2925 cm
1 arose due to C–H
Fig. 5. The CMGGOSA-I released 17.30  2.03 % of glimepiride in acidic
stretching vibrations of the –CH and –CH2 groups. Similar peaks were
conditions (pH 1.2) in 2 h. After 24 h at simulated gut pH, carriers
recorded previously [37,38]. COO
asymmetric and symmetric stretch-
released 90.59  3.28 % of the drug. Thus, nanocarriers demonstrated
ing vibrations in CMGG resulted in bands at 1588 cm
1 and 1409 cm
1,
respectively. Kundu et al. [39] identified similar peaks of carboxylate
stretching vibrations in CMGG. The galactose to the mannose (C6–O–C1)
link was particularly distinctive and measured at 1078 cm
1. Stretching
of main chain sugar ether (C–O–C) was observed at 1020 cm
1 [39,40].
The infrared spectra of CMGGOSA-I revealed peaks with characteristics
comparable to CMGG (Fig. 3b). However, additional peaks at 1651 cm
1
and 1732 cm
1 were identified as the alkenyl function and the ester
carbonyl (C– – O) stretching frequency introduced via esterification,
respectively. Similar distinctive peaks at roughly 1640 cm
1 and 1724
cm
1 in the spectra of the OSA-modified dextrin have been described
previously [14,41].
Meng et al. [42] noticed a comparable signal at 1728 cm
1 caused by
the stretching of the carbonyl groups (C– – O) of the octenyl succinate
anhydride in konjac glucomannan octenyl succinate. The peak at 3358
cm
1 represents free –OH, and its presence in the infrared spectra con-
firms that not all OH was esterified. The free hydroxyl groups could form
non-covalent hydrogen-bonding interaction with water, thus providing
stability to the CMGGOSA nanostructures in aqueous medium. Earlier
studies indicated that non-covalent hydrogen bonding interactions in a
compound could be of significance importance in terms of stability,
physicochemical and biological properties [43–45].
This was further corroborated by the degree of O-carbox-
ymethylation. CMGG had a degree of O-carboxymethyl substitution of
just 0.98  0.18. The hydroxyl groups' relative reactivity varies greatly
due to limited accessibility inside crystalline/amorphous areas and
positioning effects. Even under fully solvated conditions, the rate of
reactivity of these hydroxyl groups varies depending on a variety of
Fig. 4. TEM images of amphiphilic CMGGOSA-I nanocarriers.

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H. Yadav et al. Medicine in Novel Technology and Devices 22 (2024) 100309

Fig, 5. In vitro drug release profile of CMGGOSA-I nanocarriers in simulated Fig. 6. Preclinical efficacy of glimepiride-loaded CMGGOSA-I nanocarriers.
gastrointestinal media.
levels by 55 % in streptozotocin-treated diabetic rats after 4 h, with the
their promise as regulated drug delivery carriers. At acidic pH, the effect lasting up to 8 h. Razzaq et al. [56] found that glimepir-
octenylsuccinic acid and carboxyl groups of CMGG remained protonated, ide/β-cyclodextrin/Gelucire 44/16 nanoemulgel increased hypoglyce-
resulting in strong hydrogen bonds that compact the structure and inhibit mic activity compared to pure glimepiride over 24 h. This heightened
swelling [51], resulting in decreased drug release in the acidic medium. hypoglycemic effect could be attributed to the drug's increased solubility
As the pH increased, the carboxyl groups got ionized and triggered and permeability.
electrorepulsive forces, causing the nanocarriers to swell more. The
freshly generated cavity volume is filled with solvent molecules from the 4. Conclusion
surrounding environment [52], gradually releasing the medication over
more than 24 h. Based on the highest correlation coefficients (Table 1), The study revealed that GG was successfully converted into CMGG
the drug release was assumed to follow Higuchi kinetics. The slower and amphiphilic CMGGOSA. The amphiphilic GG produced with a
phase, as indicated by the diffusion exponent (n), could be attributed to DMAP: OSA ratio of 0.5:1 was found to be non-toxic. However, LD50
the drug's anomalous diffusion through the nanocarriers (0.43 > n < value of CMGGOSA-II, synthesized using DMAP: OSA ratio of 1:1 was
0.89). The atypical drug transport is caused by a combination of polymer found to be 908.8 mg/kg body weight. Hence, the concentration of
matrix swelling and diffusion. Because the pH in the human stomach is DMAP was found to be crucial in the synthesis of materials for biological
very acidic and near neutral in the duodenum [53], the pH-dependent use. The amphiphilic CMGGOSA-I self-assembled in water, forming
stability and swelling properties of nanocarriers may be advantageous spherical particles (430 nm diameter with a PDI of 30.7 %). With a PDI
for the oral controlled release of the medicine. value > 10 % indicated polydisperse nature of the developed nano-
Fig. 6 shows the formulations' in vivo anti-diabetic efficacy. Dey et al. carriers. With a surface charge of
19.0 mV was supposed to give a
[54] reported that a 25 % decline in blood glucose may be deemed a physically stable dispersion. The nanocarriers provided a drug entrap-
severe hypoglycemic effect. As can be seen, the pure drug suspension ment efficiency of 53.93 %. The amphiphilic nanocarriers prevented drug
reduced blood glucose levels by up to 66.54 % within 4 h. Then it steadily release for more than 24 h in simulated gastrointestinal pH, which
dropped to 28 % in 9 h. The pure drug suspension displayed strong seemed to be beneficial for controlled drug release applications under
anti-diabetic efficacy beginning at the second hour and lasting up to 9 h. varying pH environments of gastrointestinal tract. Preclinical studies
Compared to drug suspension, the CMGGOSA-I nanocarriers showed revealed that nanocarriers drastically reduced blood glucose levels for up
considerable blood glucose reducing activity at the third hour, which to 24 h However, clinical studies are needed to determine the true po-
lasted up to 24 h. The nanocarriers reduced blood glucose levels to a tential of CMGGOSA-I nanocarriers. Overall, the succinoylated CMGG
maximum of 72.17 % in 16 h, followed by a progressive reduction to nanocarriers demonstrated considerable promise in oral drug delivery
31.7 % in 24 h. A significant differences (p < 0.05) in the mean percent applications for controlling type-2 diabetes over a longer period of time.
reduction of blood glucose levels was evident. Tukey's comparison found
significant differences between diabetic control and CMGGOSA-I (p < Funding
0.001), diabetic control vs. drug suspension (p < 0.001), and drug sus-
pension vs. CMGGOSA-I (p < 0.001). The diabetes control showed no This research work was financially supported by the Biotechnology
significant reductions in blood glucose level at all. Gaber et al. [55] found Industrial Research Assistance Council (BIRAC), New Delhi, India
that polyvinylpyrrolidone K-30 nanoparticles lowered blood glucose (Project Grant No. BT/GUAR-GUM0005/01/19).

Table 1
Mathematical modeling of in vitro drug release data.
Formulation Zero order kinetics First order kinetics Higuchi kinetics Korsmeyer-Peppas model
a b 2 a b 2 a b 2 a a b 2
K0 r K1 r KH r KP n r

CMGGOSA-I 2.297 0.702 0.0345 0.760 14.05 0.861 0.1581 0.561 0.938
a
K0, K1, KH and KP indicates zero order (%/h); first order (h
1); Higuchi (%/√h) and Korsmeyer-Peppas rate constant, n ¼ diffusion exponent.
b
r2 ¼ correlation coefficient.

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